Benzothiadiazine derivatives



United States Patent M 3,234,243 BENZOTHIADIAZINE DERIVATIVES Harry Louis Yale, New Brunswick, N.J., assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Original application Mar. 25, 1959, Ser. No. 801,691, now Patent No. 3,057,862, dated Oct. 9, 1962. Divided and this application Feb. 10, 1961, Ser. No. 95,452

2 Claims. (Cl. 260-397.7)

This application is a division of my application, Serial No. 801,691, filed March 25, 1959, now US. Patent No. 3,057,862, granted October 9, 1962.

This invention relates to new benzothiadiazine derivatives, and more particularly to new trifluoromethylbenzothiadiazine-sulfonamide derivatives, one tautomer of which has the general formula YNH s o CFa (3-3 as well as the alkali metal salts thereof, wherein R is lower alkyl or carboxyl-lower alkyl, and Y is hydrogen or RCO.

The new benzothiadiazines of this invention are physiologically active compounds which possess both diuretic and antihypertensive activities. Thus, these compounds are administrable parenterally and (preferably) orally in the treatment of congestive heart failure, being uniquely suitable for the treatment of this and other conditions where both the diuretic and anti-hypertensive activities are desirable.

The compounds of this invention are prepared by the process of this invention which comprises reacting a compound of the general formula NH NH2S or? s 02 2 CFK- NH:

with either the acyl halide (preferably chloride) or acid anhydride of an acid of the formula: RCOOH, wherein R is as the above defined to yield the new intermediates of this invention of the general formula YNHSOZWqSOZNHY CF? NHCOR wherein R is the R value of the acid reactant and the s are the same or different and represent either hydrogen or the acyl radical of the acid reagent. The nature of the intermediate depends on the proportion of acid to sulr'onamide. When a large excess of acid is present, a triacylated product (both Ys are RC0) is formed. If, however, four or less molar equivalents of acid or inner anhydride (or two or less molar equivalents of normal anhydride) are used, then a mixture of the mono- (both Ys are hydrogen) and di- (one Y is RC0 and the other is hydrogen) acylated derivatives are formed. In both instances, however, the reaction is preferably conducted at an elevated temperature below about 150 C.

Upon pyrolysis the intermediates of this invention cyclize to yield the final products of this invention. This pyrolysis is accomplished by heating the intermediate to a temperature above about 200 C. The nature of the final product will depend upon the degree of acylation of the intermediate. Thus, a triacylated intermediate will yield a product wherein Y is RCO, whereas the mono- 3,234,243 Patented Feb. 8, 1965 and diacylated intermediates both yield a product wherein Y is hydrogen.

The sulfonamide reactants can be prepared as disclosed in the application of Yale et al., Serial No. 698,377, filed November 25, 1957, now Patent No. 3,040,042, granted June 19, 1962, and specifically include 5-amino-a,a,a-trifiuoro-2,4-toluenedisulfonamide, 4-amino-u,u,a-trifluoro-3, S-toluenedisulfonamide, and Z-arnino-u,a,a-trifiuoro-3,5- toluenedisulfonamide. Among the suitable acid reactants may be mentioned the *acyl halides and particularly the acid anhydrides of the lower alkanoic acids of at least two carbon atoms (e.g. acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, and enanthic anhydride) and the acyl halides and particularly the inner anhydrides of the lower alkanedioic acids (e.g. succinic anhydride, glutaric anhydride, a-ethylsuccinic anhydride, and B-methylglutaric anhydride).

The free benzothiadiazine products, thus formed, can then, if desired be treated with alcoholic alkali metal hydroxides (e.g. potassium hydroxide), whereby the alkali metal salts are formed.

The following examples illustrate the invention (all temperatures being in centigrade);

EXAMPLE 1 3-mezhyZ-6-trifluoromethyl-l ,2,4-benzothiadiazine-7- sulfomamide 1,1-di0xide (4:) Preparation of 5acetamid0-a,a,u-triflu0r0-2,4-t0'lzzenesulformmide and 5-acetamido-a,a,a-trffluoro q -acetamidosulfonyl-Z-toluenesulfonamide.A mixture of 9.6 g. (0.03 mole) of S-EmillO-a,a,a-lirii'luOIO-2,4-t0lll6l'l6dl5lllfonamide, 6.12 g. (0.06 mole) of acetic anhydride and 50 ml. of glacial acetic acid is refluxed for three hours and then concentrated in vacuo from the steam bath. The residue is a brown glass which when warmed with 50 ml. of water solidifies. The solid is filtered and recrystallized from water to give a product having 3. MP. of about 215- 218 which represents a mixture of the monoacetyl and diacetyl derivatives.

(b) Preparation of 3-methyl6-triflu0r0methyl-1,2,4- benzothiadazi eJ-sulfmmmide 1,1-di0xide.-The mixture obtained in step a is pyrolyzed by placing in an oil bath preheated to 200 and then allowing the temperature to rise to 250 during two hours. The resultant solid, upon recrystallization from water, gives about 3 g. of 3-methyl- 6-trifluoromethyl-l,2,4-benzothiadiazine-7-sulfonamide 1, l-dioxide, M.P. about BBS-340.

EXAMPLE 2 Dipotassium salt 09 3-methyl-6-triflu0r0methyI-1,2, 4-benz0th iadictziMJ-sulfonamide 1 ,1 -di0xide EXAMPLE 3 3-methyl-7-trifluor0methyl-I,2,4-benz0thiadiazine- 5 -sulf0na mide 1,1 dioxide Following the procedure of Example 1, but substituting 9.6 g. of 4-amino-a,a,a-trifiuoro-3,S-toluenedisulfonamide for the 5-amino-a,a,a-trifluoro-ZA-toluenedisulfonamide, a

mixture of the mono and diacetyl derivatives are first formed, from which 3-methyl-7-trifiuoromethyl-1,2,4- benzothiadiazine-S-sulfonamide 1,1-dioxide is obtained.

EXAMPLE 4 3 -metl2y l-5 -tri fluorome thiy l-l ,2,4-l7enz0thiadiazine- 7-sulf0namide 1,1-dioxide EXAMPLE 5 Following the procedure of Example 1, but substituting- 7.8 g. (0.06 mole) of propionic anhydride for the acetic anhydride and 50 ml. of propionic acid for the acetic acid in step a, there is first obtained a mixture of 5-propionamido-a ,m-trifiuoro-2,4-toluenedisulfonamide and 5- propionamido-a,a,u-trifiuoro 4 propionamidosulfonyl- 2-toluenesulfonamide, and then by the procedure of step b, '3 ethyl 6 trifluoromethyl-1,2,4-benzothiadiazine- 7-sulfonamide 1,1-dioxide. a

Similarly, valeric arrhydride and enanthic anhydride, substituted in equivalent amount, yield first a mixture of the'S-mono and 4,5-diacy1ated derivatives, and then 3-nbutyl 6 trifluoromethyl 1,2,4 benzothiadiazine 7- sulfonamide 1,1-dioxide and 3-n-hexyl-6-trifluoromethyll,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, respectively.

EXAMPLE 6 7-.s"ul dmyl-6-trifluoromethyl-1,2,4-benz0thiadiazine 3-propi0nic acid 1,1-dioxide (a) Prparation f fi-(2,4-disulfamyl-S-triflnoromethyl-phenylcarbamyl)-pr0pi0nic acid.-A mixture of 32 g. (0.1 mole) of -amino-u,a,a-trifiuoro-2,4-toluenedisulfonamide, and 10 g. (0.1mole) of succinic anhydride is fused for two hours in an oil bath maintained at 175. The resultant product is recrystallized from water to give about 23 g. of fl-(2,4-disulfamyl-S-trifluoromethyl-phenylcarbamyl)propionic acid, M.P. about 260-262".

v (b) Preparation of 7- ulfamyl-6-trifluor0methyl-1,2,4- benzothiadiazine-3-pr0pi0nic acid 1,1-di0xide.--23 g. of ,8-(2,4 disulfamyl 5 trifluoromethyl-phenylcarbamyl)- propionic acid is fused for one hour in an oil bath maintained at 240-250". The product is decolorized by refluxing with activated charcoal in 600 ml. of acetone solution. The filtered acetone solution is concentrated to 150 ml. and diluted with 600 ml. of water. The product crystallizes to yield, after drying, about 6.7 g. of 7-sulfamyl 6 trifluoromethyl 1,2,4 benzothiadiazine 3- propionic acid 1,1-dioxide, M.P. about 334-335 Similarly, by substituting an equivalent amount of glutaric anhydride, p-methylglutaric anhydride, and oi-ethyl succinic anhydride for the succinic anhydride in step a of Example '6,jthere is first obtained 'y-(2,4-disulfamyl-5- trifluoromethyl-phenylcarbamyl)butanoic acid; 'y-(2,4-disulfamyl 5 trifluoromethyl-phenylcarbamyl) B methylbutanoic acid, and ,3-(2,4-disulfamyl-S-trifluoromethylphenylcarbamyl)-u-ethylpropionic acid, respectively; and then by the procedure of step b, 7-sulfamyl-6-trifluoromethyl 1,2,4 benzothiadiazine 3 butanoic acid, 7-

sulfamyl 6 trifluoromethyl 1,2,4 benzothiadiazine- 3-/3-methylbutanoic acid, and 7-sulfamyl-6-trifiuoromethyl-1,2,4-benzothiadiazine-3-u-ethy1propionic acid, respectively. y

p 7 EXAMPLE 7 g 7-acetylsiilfamyl-3-methyl-6-triflu0r0mezhyl-1,2,4- benzothiadiazine 1,1-dioxide (b) Preparation of 5-acetamid0-oi,u,cx-trifluoro-Z,4-di- 4 acetamidosulfonyltoluene -A mixture of 25 g. (0.078 mole) of 5 ZIII'liIlO-OL,DL,u-tllflll01'0 2,4 toluenedisulfonamide and g. (0.91 mole) of acetic anhydride is heated under reflux for two hours, cooled, and the crystalline solid filtered on a sintered glass funnel. Recrystallization from aqueous acetonitrile (2:1) gives 5-acetarnidO-oz,0t,0t-tl1flll0l0 2,4 diacetamidosulfonyltoluene, M.P. about 200-202".

(b) Preparation of 7-acetylsulfamyl-3-methyl-6-trifluoromethyl-I,2,4-bcnz0thiadiazine 1,1-cli0xide.l5 g. of 5 acetamido ot,ot,oz trifluoro-2,4-diacetamidosulfonyltoluene is pyrolyzed for two hours in an oil bath at 215- 225". The pyrolysis product is dissolved in 500 ml. of boiling acetone, the solution is decolorized with activated charcoal, filtered and the filtrate concentrated to dryness. The residual white solid is recrystallized from aqueous isopropanol (1:1) to give about 4.5 g. of 7-acetylsul famyl 3 methyl 6 trifluoromethyl 1,2,4 benzothiadiazine 1,1-dioxide, M.P. about 285-287.

EXAMPLE 8 3-ethyl-6-trifluor0methy l-1 ,2,4-bcnz0thiadiazine- 7 -sul fonamide 1,1-dioxide (a) Preparation of 5-pr0pionamid0-a,u,oc-triflu0r0-2,4- di-propionamidosulfonylt0lucne.--A mixture of 25 g. (0.08 mole) of 5 amino-a,oc,a-trifluoro 2,4 toluenedisulfonamide and 104 g. (0.8 mole) of propionic anhydride is heated under reflux for two hours and then concentrated to dryness. The crude product isrecrystallized from aqueous acetonitrile (9:1) to give an analytical sample of 5-propionamido-a,ci,u-trifiuoro-2,4-dipropionamidosulfonyltoluene, M.P. about 227-229.

(b) Preparation of 3-ethyl-fi-trifluoromethyl-l,2,4-benzothiadiazine-7-sulfonamide 1,1-di0xide.31 g. of 5-propionamido-a,a,a-trifluoro 2,4 dipropionamido-sulfonyltoluene is dissolved in 310 ml. of Dowtherm A preheated to 210. The solution is kept two hours at 210215, cooled, and the crystalline solid filtered. The solid is washed with ethyl ether and recrystallized from aqueous isopropanol (1:1) to give about 10 g. of 3-ethyl-6-trifluoromethyl 1,2,4 benzothiadiazine 7 sulfonamide 1,1-dioxide, M.P. about 345-347 (dec.).

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. 5 (carboxyl-lower alkanoylamido) oi,a, x trifluoro-2,4-toluenedisulfonamide.

2. ,8 (2,4 disulfamyl 5 trifluoromethyl-phenylcarbamyD-propionic acid.

References Cited by the Examiner UNITED STATES PATENTS 2,240,496 5/1941 Dvornikoff 260-3971 2,809,194 10/ 1957 Novello 260-397.7 2,894,948 7/ 1959 De Stevens et a1. 260-397.7 2,910,476 10/1959 Novello 260-397.7 2,965,675 12/1960 Novello 260397.7 3,040,042 6/ 1962 Yale et a1. 260243 3,066,156 11/1962 Ziegler 260397.7 3,081,301 3/1963 De Stevens et al 260-243 I OTHER REFERENCES Crossley et al.: Journ. Am. Chem. Soc, volume 61, pages 2951-55 (1939).

Novello et al.: Journ. Am. Chem. Soc, volume 79, pages 2028-29 (1957).

Rujagopalon: Chemical Abstracts, volume 38, pages 1217-18 (1944).

WALTER A. MODANCE, Primary Examiner.

IRVING MARCUS, JOHN D. RANDOLPH, NICHO- LAS S. RIZZO, Examiners.

JAMES W. ADAMS, Assistant Examiner. 

1. 5-(CARBOXYL-LOWER ALKANOYLAMIDO)-A,A,A-TRIFLUORO-2,4-TOLUENEDISULFONAMIDE.
 2. B-(2,4-DISULFAMYL-5-TRIFLUOROMETHYL-PHENYLCARBAMYL)-PROPIONIC ACID. 